All complexes of T cell receptors (TCRs) bound to peptide-major histocompatibility complex (pMHC) molecules assume a stereotyped binding 'polarity', despite wide variations in TCR-pMHC docking angles. However, existing TCR-pMHC crystal structures have failed to show broadly conserved pairwise interaction motifs. Here we determined the crystal structures of two TCRs encoded by the variable beta-chain 8.2 (V(beta)8.2), each bound to the MHC class II molecule I-A(u), and did energetic mapping of V(alpha) and V(beta) contacts with I-A(u). Together with two previously solved structures of V(beta)8.2-containing TCR-MHC complexes, we found four TCR-I-A complexes with structurally superimposable interactions between the V(beta) loops and the I-A alpha-helix. This examination of a narrow 'slice' of the TCR-MHC repertoire demonstrates what is probably one of many germline-derived TCR-MHC interaction 'codons'.

HLA-B * 4402 and B * 4403 are naturally occurring MHC class I alleles that are both found at a high frequency in all human populations, and yet they only differ by one residue on the ␣ 2 helix (B * 4402 Asp156 → B * 4403 Leu156). CTLs discriminate between HLA-B * 4402 and B * 4403, and these allotypes stimulate strong mutual allogeneic responses reflecting their known barrier to hemopoeitic stem cell transplantation. Although HLA-B * 4402 and B * 4403 share Ͼ 95% of their peptide repertoire, B * 4403 presents more unique peptides than B * 4402, consistent with the stronger T cell alloreactivity observed toward B * 4403 compared with B * 4402. Crystal structures of B * 4402 and B * 4403 show how the polymorphism at position 156 is completely buried and yet alters both the peptide and the heavy chain conformation, relaxing ligand selection by B * 4403 compared with B * 4402. Thus, the polymorphism between HLA-B * 4402 and B * 4403 modifies both peptide repertoire and T cell recognition, and is reflected in the paradoxically powerful alloreactivity that occurs across this "minimal" mismatch. The findings suggest that these closely related class I genes are maintained in diverse human populations through their differential impact on the selection of peptide ligands and the T cell repertoire.Key words: class I histocompatibility molecules • antigen presentation • crystallography • X-ray diffraction • graft rejection • polymorphism protective immunity against microbes (1-3). HLA alleles can differ from each other by only a single amino acid ("micropolymorphism") or by Ͼ 30 amino acids (4). It has been suggested that there are nine major HLA class I "supertypes," or clusters of alleles, that each possess a unique broad specificity for common anchor motifs in antigenic peptides (5). Alleles from each of these supertypic families are distributed in virtually all human populations and account

T helper type 17 (TH-17) cells, together with their effector cytokines including interleukin 17 (IL-17) family members, are emerging as key mediators of chronic inflammatory and autoimmune disorders. Here we present the crystal structure of a 1:2 complex of IL-17RA bound to IL-17F. The manner of complex formation is unique for cytokines, and involves two fibronectin-type domains of IL-17RA engaging IL-17 within a groove between the IL-17 homodimer interface in a knob-and-hole fashion. The first receptor-binding event to the IL-17 cytokines modulates the affinity and specificity of the second receptor-binding event, thereby promoting heterodimeric versus homodimeric complex formation. IL-17RA utilizes a common recognition strategy to bind to several IL-17 family members, allowing it to potentially act as a shared receptor within multiple different signaling complexes.